The recent workshop on inflammation and periodontal diseases organized by American Academy of Periodontology (AAP) has proposed "use of statins and targeted anti-inflammatory therapies in patients with periodontal disease to modulate inflammation and, hence, lower risk for systemic conditions such as atherosclerosis" as one of the clinical initiatives in the medium term (5 to 10 years). Although a recent study has shown that patients with periodontal disease who were taking statins had significantly less diseased periodontal tissue than those who weren't on the drugs, it remains unknown how statin use is associated with periodontal disease in diabetic patients. The study in diabetic patients is important since periodontal disease is more prevalent and severe in diabetic patients than that in nondiabetic patients. Furthermore, it remains unknown how statin use is associated with periodontal expression of inflammatory cytokines and matrix metalloproteinases (MMPs) that are essential for developing periodontal disease. From our recent NIDCR-funded study, we found that high glucose amplified lipopolysaccharide (LPS)-elicited immune responses from mononuclear cells. We also found that simvastatin effectively suppresses high glucose-boosted, LPS-induce expression of inflammatory cytokines and MMPs. In addition, in our studies to explore the molecular mechanisms involved in statin's action, we found that statin inhibited high glucose and LPS- stimulated transcription factor AP-1 activity, which is critical for MMP expression. However, it remains unclear how statin inhibits AP-1 activity. Based on these findings, we proposed three specific aims: 1. To determine the effects of simvastatin on periodontal inflammation and alveolar bone loss in nondiabetic and diabetic animal models. 2. To determine the relationship between statin use and periodontal disease as well as periodontal inflammatory cytokine and MMP expression in nondiabetic and diabetic patients. 3. To determine the signaling and molecular mechanisms by which statin inhibits high glucose/LPS-stimulated transcription factor AP-1 activity in mononuclear cells. We hypothesize that statin administration is associated with a reduction of periodontal tissue inflammation in both nondiabetic and diabetic animals and patients, but the reduction in diabetic patients is greater. We also hypothesize that statin inhibits AP-1 activity by blocking expression and activation of c-Fos. The goal of this research project is to provide novel information for better understanding of the effects of statin on periodontal disease in both nondiabetic and diabetic patients, which is important for potential use of statins in treatment of periodontal disease as proposed by AAP. PUBLIC HEALTH RELEVANCE: By combining animal, patient and molecular biology studies, the goal of this research project is to provide novel information for better understanding of anti-inflammatory effects of statin on periodontal disease and tissue inflammation in both nondiabetic and diabetic patients, which is essential for clinical use of statins in the treatment of periodontal disease as proposed by American Academy of Periodontology as one of the clinical initiatives in the medium term (5 to 10 years).